The overall aim of this project is to gain insight into the inflammatory, oxidative and endothelial control mechanisms underlying the cardiovascular effects of short- and long-term exposure to traffic-associated fine particulate matter (PM). This will be accomplished by investigating in a human population the differential susceptibility to PM effects associated with specific genetic polymorphisms that involve these key mechanistic pathways. The aim will be addressed by making efficient use of an ongoing cohort study of atherosclerotic cardiovascular disease, the Multi-ethnic Study of Atherosclerosis (MESA), and several MESA ancillary studies for which PM and traffic exposure data, genotyping data, and data on multiple relevant cardiovascular endpoints are being collected. The specific aims of this project are to gain insight into the mechanisms underlying the cardiovascular effects of traffic-associated PM by: 1) making use of the MESA cohort to determine whether specific genetic polymorphisms in key pathways regulating inflammation, oxidative stress, and endothelial function modify: a) the long-term exposure effects of traffic-associated PM on the development and progression of atherosclerosis using measures that include arterial wall thickness and coronary artery calcium, and b) the short-term exposure effects of these PM components on functional cardiovascular and mechanistic endpoints, including carotid distensibility, pulse wave measures, endothelial function, and plasma markers of inflammation and endothelial activation; 2) validating the findings from Specific Aim 1 on a newly genotyped sample of MESA participants; and 3) making use of the toxicological findings from Center Project 5 on novel genetic polymorphisms of interest by investigating the modifying effects of these additional polymorphisms on long-term and short-term PM exposure effects, and validating these findings on the newly genotyped human population sample. This project integrates across all projects of this center through the choice of both the specific genetic polymorphisms to be investigated in common with other projects, and the specific cardiovascular endpoints to be studied. Further integration is evident in the use of findings from other center projects to guide the choice of polymorphisms to study. Because it employs a representative human population sample of several U.S. ethnic groups to study a pervasive and important inhalational exposure and a common disease, this project has direct public health relevance. It is currently not known which sources and chemical components of PM are most responsible for its cardiovascular effects, or which of several plausible mechanisms underlie these effects. By contributing to our understanding of mechanisms and the identification of exposure sources of most concern, this project can allow more directed and efficient public health policies to be considered.